Rapid inhibition of pyruvate dehydrogenase: an initiating event in high dietary fat-induced loss of metabolic flexibility in the heart.
Rapid inhibition of pyruvate dehydrogenase: an initiating event in high dietary fat-induced loss of metabolic flexibility in the heart.
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DOI：
10.1371/journal.pone.0077280
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Szweda LI
中科院分区：
文献类型：
--
作者：
Crewe C;Kinter M;Szweda LI
心脏功能依赖于脂肪酸和葡萄糖氧化之间的能量生产切换能力，以响应底物可用性和能量应激的变化。在肥胖和糖尿病患者中，对脂肪酸依赖的增加和代谢灵活性的降低被认为是导致心血管疾病发展的原因。研究了心脏线粒体在饮食诱导的代谢不灵活性中的作用机制。小鼠分别饲喂高脂或低脂饮食1 d、1周和20周。从喂食高脂肪饮食的小鼠中分离的心脏线粒体显示出利用糖酵解衍生的底物丙酮酸的能力减弱。这种反应是迅速的，发生在饮食的第一天，并持续长达20周。丙酮酸脱氢酶激酶4表达的选择性增加和丙酮酸脱氢酶的抑制是迅速抑制丙酮酸利用的原因。一个重要的结果是，当线粒体在脂肪酸存在下呼吸时，丙酮酸脱氢酶对抑制敏感。此外，丙酮酸脱氢酶激酶4的表达增加先于任何观察到的饮食诱导的葡萄糖转运蛋白4型和糖酵解酶水平的降低，以及Akt磷酸化判断的胰岛素信号传导。重要的是，高脂肪饮食1周后明显的胰岛素信号减弱在丙酮酸脱氢酶激酶4敲除小鼠中没有发生。饮食干预导致丙酮酸脱氢酶激酶4水平的迅速下降和丙酮酸脱氢酶活性的恢复，这表明了一种额外的调节形式。最后，一夜禁食引起的代谢反应类似于高脂肪饮食引起的代谢变化。因此，我们的数据表明，饮食诱导的丙酮酸脱氢酶的抑制可能是葡萄糖氧化降低和心脏对脂肪酸产生能量的依赖增加的起始事件。
Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production.
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